10.1007/s11060-010-0121-0</TIT= LE> <META http-equiv=3DContent-Type content=3D"text/html; = charset=3DISO-8859-1"><LINK=20 href=3D"http://www.springerlink.com/config/css/A++_common.css" = type=3Dtext/css=20 rel=3DstyleSheet><LINK=20 href=3D"http://www.springerlink.com/config/css/content_A++_SpringerLink.c= ss"=20 type=3Dtext/css rel=3DstyleSheet> <META content=3D"MSHTML 6.00.6000.17023" name=3DGENERATOR></HEAD> <BODY class=3Dfor-print> <TABLE cellPadding=3D2 border=3D1> <TBODY> <TR class=3Dheader> <TD>Journal of Neuro-Oncology</TD></TR> <TR> <TD>=A9 Springer Science+Business Media, = LLC. 2010</TD></TR> <TR> <TD>10.1007/s11060-010-0121-0</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Clinical Study - Patient Study</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Rebound tumour progression = after the=20 cessation of bevacizumab therapy in patients with recurrent high-grade = glioma=20 </DIV> <P class=3DAuthorGroup>Richard M. Zuniga<SUP>1 <A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#ContactOfAuthor1"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/contact.gif" = border=3D0></A></SUP>, Roy Torcuator<SUP>1, 2</SUP>,=20 Rajan Jain<SUP>3</SUP>, John Anderson<SUP>4</SUP>,=20 Thomas Doyle<SUP>4</SUP>, Lonni Schultz<SUP>5</SUP> and=20 Tom Mikkelsen<SUP>1, 2</SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Henry Ford Health System, Hermelin = Brain Tumor=20 Center, 2799 W Grand Blvd, Detroit, MI 48202,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff2></A>(2) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, Henry Ford = Health=20 System, Detroit, MI, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff3></A>(3) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neuroradiology, Henry = Ford=20 Health System, Detroit, MI, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff4></A>(4) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Medical Oncology, Henry = Ford=20 Health System, Detroit, MI, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff5></A>(5) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Biostatistics and = Research=20 Epidemiology, Henry Ford Health System, Detroit, MI,=20 USA</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor1></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/contact.gif" = border=3D0></TD> = <TD><STRONG>Richard </STRONG><STRONG>M. </STRONG><STRONG>Zuniga= </STRONG><STRONG></STRONG><BR><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:rickzunigaperu@hotmail.com">rickzunigaperu@hotmail.com</A>= </TD></TR></TBODY></TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>2 July 2009 <STRONG>Accepted:=20 </STRONG>25 January 2010 <STRONG>Published online:=20 </STRONG>12 February 2010 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract </SPAN>After withdrawal of = bevacizumab=20 in patients with recurrent high-grade glioma, we have observed a rapid = tumour=20 re-growth or =93rebound=94 radiographic phenomenon with accelerated = clinical=20 decline. We retrospectively reviewed 11 patients treated at the Henry = Ford=20 Hermelin Brain Tumor Center with recurrent high-grade glioma who = demonstrated a=20 rebound progression pattern after the discontinuation of bevacizumab. = The=20 original tumour area-of-enhancement increased by a mean of 158%, when = compared=20 to the rebound magnetic resonance imaging. After rebound, no patients = (0/8)=20 showed a response to next-line treatments that did not include = bevacizumab. The=20 median survival of those re-treated with bevacizumab was 149 and = 32 days=20 for those who received other regimens. Abrupt discontinuation of = bevacizumab=20 after recurrence often leads to a dramatic rebound phenomenon and rapid = clinical=20 decline. Slow tapering of the bevacizumab dose after tumour progression = may=20 prevent this from occurring and improve responsiveness to next-line = therapies.=20 </DIV> <P class=3DKeyword><SPAN=20 class=3DKeywordHeading>Keywords </SPAN>Glioma - Beva= cizumab - Rebound - Recurrent=20 glioma - Glioblastoma </P> <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> <P class=3D"">High-grade gliomas are aggressive tumours with a poor = prognosis even=20 after treatment with standard post resection chemo-radiation. These = tumours=20 exhibit diffuse parenchymal infiltration and are highly angiogenic. The = landmark=20 clinical trial by Stupp et al., described a median survival of=20 14.6 months and a 2-year survival rate of 26% for those with = glioblastoma=20 multiforme (GBM) after undergoing surgical resection with subsequent = external=20 beam radiation therapy plus temozolomide as first line therapy [<CITE><A = href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR1">1</A></CITE>].=20 </P> <P class=3D"">Due to the highly infiltrative nature of these tumours, = recurrence=20 is essentially inevitable. After first-line treatment failure, = historical data=20 reports a dramatic decrease in overall survival (OS) to 25 weeks = for GBM=20 and 47 weeks for AA [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR2">2</A></CITE>].=20 However, agents that target multiple signaling pathways and critical = growth=20 factors essential for tumour angiogenesis have become a major focus of = interest=20 in experimental clinical studies. Vascular endothelial growth factor = (VEGF) is a=20 potent growth factor produced by tumour and stromal cells that = facilitates=20 migration, proliferation and survival of endothelial cells making it = essential=20 in tumour angiogenesis [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR3">3</A></CITE>].=20 VEGF is heavily overexpressed in high-grade gliomas and is directly = correlated=20 with tumour growth rate, metastatic potential and poor outcome [<CITE><A = href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR4">4</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR6">6</A></CITE>].=20 </P> <P class=3D"">Bevacizumab, an anti-VEGF recombinant humanized monoclonal = antibody,=20 has been found to be active in other solid tumours, such as breast, = non-small=20 cell lung and colorectal cancer, and renal cell cancer [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR7">7</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR10">10</A></CITE>].=20 Over the past several years bevacizumab has been studied in high-grade = gliomas=20 with encouraging results. A number of reports have described an = excellent=20 improvement in radiographic response and clinical outcome in patients = treated=20 with bevacizumab and the cytotoxic agent, irinotecan, for recurrent = high-grade=20 gliomas [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR11">11</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR14">14</A></CITE>].=20 Despite these encouraging results, the remarkable and rapid radiographic = response seen on MRI does not appear to lead to a proportional = improvement in=20 survival and very few show any response at all to next-line therapy = after=20 bevacizumab failure [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR15">15</A></CITE>].=20 </P> <P class=3D"">As we gain more experience using this agent in high-grade = gliomas,=20 we also learn more about what occurs after treatment failure. Mancuso=20 et al. conducted a laboratory research study with mice to address = the=20 reversibility of VEGF inhibition after cessation of anti-VEGF therapy. = It was=20 noted that even after a 50=9660% reduction of tumour vascularity, = =93empty sleeves=20 of basement membrane were left behind.=94 By day 7 after drug = withdrawal, tumours=20 were fully re-vascularized, suggesting that these remaining empty = sleeves of=20 basement membrane and pericytes are responsible for this tumour=20 revascularization. These basement membranes also serve as angiogenic = growth=20 factor storage sites and =93tracks=94 for tumour vascular regrowth = [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR16">16</A></CITE>].=20 </P> <P class=3D"">This rapid tumour re-growth has also been noted in some of = our=20 patients after treatment failure with bevacizumab. A dramatic = =93rebound=94=20 radiographic recurrence phenomenon has been observed that appears to = lead to a=20 rapid clinical decline. It has not been defined who is susceptible to = this=20 rebound effect and traditional radiographic criteria used to assess = response are=20 not good indicators of effective tumour control in patients treated with = VEGF=20 inhibitors [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR14">14</A></CITE>],=20 and cannot predict who may present with this aggressive form of = progression.=20 </P> <P class=3D"">These observations led us to conduct a retrospective = review of=20 selected patients with the objective of quantitatively describing this = rebound=20 phenomenon along with its clinical implications in terms of patient = outcome and=20 response to subsequent therapy regimens. </P></DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Methods</DIV> <DIV class=3D""><A name=3DSec3></A> <DIV class=3DHeading3>Patient selection</DIV> <P class=3D"">We performed a retrospective search of the Henry Ford = Hospital,=20 Hermelin Brain Tumor Center database for all patients with recurrent = high-grade=20 glioma treated with bevacizumab-based regimens from 11/15/2005 to = 12/31/2008 and=20 found 53 patients. At the time of analysis, 40 patients had progressed = while on=20 bevacizumab and required discontinuation of the drug. We identified 11 = patients=20 within this group who presented with a rebound progression of disease = (PD)=20 pattern after the discontinuation of bevacizumab. All of the patients = were=20 required to have a minimum KPS score of 60%, normal kidney and adequate = bone=20 marrow function to be eligible for initial treatment with bevacizumab.=20 </P></DIV> <DIV class=3D""><A name=3DSec4></A> <DIV class=3DHeading3>Treatment</DIV> <P class=3D"">Each patient was treated with bevacizumab plus irinotecan = IV=20 infusions given once every two weeks. The bevacizumab was administered = at a dose=20 of 10 mg/kg. The dosing for irinotecan was dependent on whether the = patients were receiving enzyme-inducing anti-epileptic drugs (EIAED). If = they=20 were taking an EIAED, they received 340 mg/m<SUP>2</SUP> of = irinotecan once=20 every two weeks. If they were not taking EIAEDs they received=20 125 mg/m<SUP>2</SUP> of irinotecan every two weeks. Three treatment = sessions constituted one-six-week cycle. After bevacizumab treatment = failure,=20 eight out of the 11 patients received next-line treatment regimens that = did not=20 include bevacizumab (erlotinib, imatinib, hydroxyurea, sirolimus, = fractionated=20 stereotactic radiotherapy and the clinical trial investigational drugs = MLN-518=20 [tyrosine kinase inhibitor] and EM-1421). After the demonstration of = rebound=20 recurrence on MRI, the three remaining patients were re-started on=20 bevacizumab-based regimens (i.e., one patient received irinotecan, one = received=20 carboplatin and one received alternate-dose temozolomide). </P></DIV> <DIV class=3D""><A name=3DSec5></A> <DIV class=3DHeading3>MRI assessment</DIV> <P class=3D"">The MRIs for all 11 patients were reviewed by the authors = and a=20 neuro-radiologist. All 11 patients had high quality and acceptable=20 post-gadolinium T1 weighted and FLAIR MRI sequences. We quantitatively = measured=20 and compared the largest cross-sectional area of enhancement and of = abnormal=20 FLAIR signal seen on MRI at four different time points: (1) Prior to the = initiation of bevacizumab; (2) after one cycle of bevacizumab; (3) at = the time=20 of bevacizumab failure, and (4) after discontinuation of the drug. </P> <P class=3D"">Treatment failure and response was defined using the = revised=20 MacDonald criteria [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR17">17</A></CITE>].=20 A new focus of enhancement outside of at least a 2-cm margin from the = index=20 lesion was defined as =93distant=94 PD. An increase of over 25% of the = largest=20 cross-sectional area of enhancement of the index lesion constituted a = local=20 pattern of PD. Rebound PD was defined as an increase of at least 50% in = the=20 largest cross-sectional area of enhancement on the rebound MRI compared = to the=20 one performed at the time of bevacizumab failure. The revised MacDonald = criteria=20 define complete response (CR) as complete resolution of all detectable = areas of=20 enhancement. Partial response (PR) is defined as at least a 50% decrease = in the=20 largest cross-sectional tumour area. All others were labeled stable = disease=20 (SD). </P></DIV> <DIV class=3D""><A name=3DSec6></A> <DIV class=3DHeading3>Measurements, endpoints, and statistical = analysis</DIV> <P class=3D"">All patients underwent serial interval MRIs with and = without=20 gadolinium contrast every 6=968 weeks after the discontinuation of=20 bevacizumab. Our end points include the median patient OS after the = rebound MRI=20 as well as the radiographic response rate when started on next-line = therapy.=20 </P> <DIV class=3DPara> <DIV class=3D"">Treating clinicians at our institution reported = end-point=20 outcomes. We determined the rate of response in patients who were = re-started on=20 bevacizumab, as well as those who were started on a different salvage = treatment=20 regimen. The Kaplan=96Meier method was used for end-point estimation = (Fig. <A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#Fig1">1</A>).=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2010_121_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/MediaObjects/= 11060_2010_121_Fig1_HTML.gif"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 1 </SPAN>Kaplan=96Meier showing=20 overall survival </DIV> <HR> </DIV></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec7></A> <HR> <DIV class=3Dheading2>Results</DIV> <DIV class=3D""><A name=3DSec8></A> <DIV class=3DHeading3>Patient population</DIV> <DIV class=3DPara> <DIV class=3D"">We reviewed 53 patients with recurrent high-grade glioma = treated=20 with bevacizumab-based regimens. At the time of analysis 11 (eight men = and three=20 women) out of the 40 patients who failed bevacizumab therapy because of = tumor=20 recurrence, demonstrated radiographic rebound PD after the = discontinuation of=20 bevacizumab. Of these 11 patients, eight had primary GBM, two had = secondary GBM,=20 and one had anaplastic oligodendroglioma. All had received at least one = prior=20 chemotherapy regimen before the administration of bevacizumab. The = median age of=20 our patient population was 56 years of age. The median baseline KPS = score=20 at the time of bevacizumab failure was 90%. The median KPS at the time = of=20 radiographic rebound was 60%. One of the patients rebounded on the first = MRI=20 after complete surgical resection of the area of enhancement seen at the = time of=20 bevacizumab failure. Patient characteristics are shown in Table <A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#Tab1">1</A>.<A=20 name=3DTab1></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 1 </SPAN>Demographic and=20 Medical History Information (<I>n</I> =3D 11) </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Variable</P></TH> <TH align=3Dleft> </TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Age</P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Mean (SD)</P></TD> <TD align=3Dleft> <P class=3D"">53.5 (11.3)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Median (Range)</P></TD> <TD align=3Dleft> <P class=3D"">56 (37 to 72)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Sex, N (%)</P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Male</P></TD> <TD align=3Dleft> <P class=3D"">8 (72.7%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Female</P></TD> <TD align=3Dleft> <P class=3D"">3 (27.3%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Pathology, N (%)</P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> GBM</P></TD> <TD align=3Dleft> <P class=3D"">8 (72.7%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Anaplastic oligodendroglioma</P></TD> <TD align=3Dleft> <P class=3D"">1 (9.1%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Mixed anaplastic oligoastrocytoma, = GBM</P></TD> <TD align=3Dleft> <P class=3D"">1 (9.1%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Oligodendroglioma, GBM</P></TD> <TD align=3Dleft> <P class=3D"">1 (9.1%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">KPS at start of Avastin</P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Median</P></TD> <TD align=3Dleft> <P class=3D"">90</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Range</P></TD> <TD align=3Dleft> <P class=3D"">60=96100</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">KPS at Rebound</P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Median</P></TD> <TD align=3Dleft> <P class=3D"">60</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Range</P></TD> <TD align=3Dleft> <P class=3D"">50=9690</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Survival after Rebound</P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Median</P></TD> <TD align=3Dleft> <P class=3D"">7 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> 95% confidence interval</P></TD> <TD align=3Dleft> <P class=3D"">4.3=9626.6 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Overall Survival (OS)</P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Median</P></TD> <TD align=3Dleft> <P class=3D"">10.8 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> 95% confidence interval</P></TD> <TD align=3Dleft> <P = class=3D"">7.7=9616.2 months</P></TD></TR></TBODY></TABLE></DIV></DI= V></DIV> <DIV class=3D""><A name=3DSec9></A> <DIV class=3DHeading3>Response analysis</DIV> <DIV class=3DPara> <DIV class=3D"">We assessed radiographic response to next-line treatment = after=20 bevacizumab failure. Prior to beginning therapy with bevacizumab, the = mean=20 cross-sectional area of contrast enhancement and of abnormal FLAIR = signal was=20 14.03 and 43.9 cm<SUP>2</SUP>, respectively. All but one of the 11 = patients=20 demonstrated at least partial radiographic response (PR) after one cycle = of=20 bevacizumab therapy. From the time of bevacizumab failure to the = subsequent=20 rebound MRI the mean largest cross-sectional area of enhancement and = increased=20 FLAIR signal went from 18.53 to 36.24 cm<SUP>2</SUP> and 43.38 to=20 64.39 cm<SUP>2</SUP>, respectively (Fig. <A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#Fig2">2</A>).=20 The mean interval between the MRI performed at the time of bevacizumab = failure=20 and the rebound MRI was 6.1 weeks (Table <A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#Tab2">2</A>).=20 <DIV class=3DFigure><A name=3DFig2></A><IMG=20 alt=3DMediaObjects/11060_2010_121_Fig2_HTML.jpg=20 src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/MediaObjects/= 11060_2010_121_Fig2_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 2 </SPAN>Original = tumor area=20 seen on post-Gd T1 weighted (<B>a</B>) and FLAIR MRI (<B>e</B>) = sequences prior=20 to initiating therapy with bevacizumab in a patient with recurrent = high-grade=20 glioma. Post-Gd T1 weighted (<B>b</B>) and FLAIR MRI (<B>f</B>) = sequences that=20 demonstrate partial response after 1 six-week cycle of treatment with=20 bevacizumab. Post-Gd T1 weighted (<B>c</B>) and FLAIR MRI (<B>g</B>) = sequences=20 at the time of bevacizumab failure and subsequent cessation of = bevacizumab=20 therapy. Post-Gd T1 weighted (<B>d</B>) and FLAIR MRI (<B>h</B>) = sequences at=20 the time of =93rebound=94 progression demonstrating a dramatic increase = in area of=20 enhancement and abnormal FLAIR signal 6 weeks after cessation of = therapy=20 with bevacizumab </DIV> <HR> <A name=3DTab2></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 2 </SPAN>Descriptive=20 statistics for time between MRIs, contrast and FLAIR measurements at = each MRI=20 and change in contrast and FLAIR measurements between MRIs </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dchar char=3D"."> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Variable</P></TH> <TH align=3Dleft> <P class=3D"">Mean</P></TH> <TH align=3Dleft char=3D"."> <P class=3D"">S.D.</P></TH> <TH align=3Dleft> <P class=3D"">Median</P></TH> <TH align=3Dleft> <P class=3D"">Range</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Time</P></TD> <TD align=3Dleft> </TD> <TD align=3Dleft char=3D"."> </TD> <TD align=3Dleft> </TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Start of to after 1st cycle = bevacizumab</P></TD> <TD align=3Dleft> <P class=3D"">8.1 weeks</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">3.6</P></TD> <TD align=3Dleft> <P class=3D"">8 weeks</P></TD> <TD align=3Dleft> <P class=3D"">4=9617.9 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> After 1st cycle of bevacizumab to = progression</P></TD> <TD align=3Dleft> <P class=3D"">23.6 weeks</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">13.4</P></TD> <TD align=3Dleft> <P class=3D"">22.9 weeks</P></TD> <TD align=3Dleft> <P class=3D"">6=9649.9 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Progression to rebound</P></TD> <TD align=3Dleft> <P class=3D"">6.1 weeks</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">2.5</P></TD> <TD align=3Dleft> <P class=3D"">6 weeks</P></TD> <TD align=3Dleft> <P class=3D"">3=9610 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Contrast</P></TD> <TD align=3Dleft> </TD> <TD align=3Dchar char=3D"."> </TD> <TD align=3Dleft> </TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Start of bevacizumab</P></TD> <TD align=3Dleft> <P class=3D"">14.03</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">7.91</P></TD> <TD align=3Dleft> <P class=3D"">15.66</P></TD> <TD align=3Dleft> <P class=3D"">3.64=9628.6</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> After 1st cycle of bevacizumab</P></TD> <TD align=3Dleft> <P class=3D"">8.97</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">6.23</P></TD> <TD align=3Dleft> <P class=3D"">8.40</P></TD> <TD align=3Dleft> <P class=3D"">1.08=9617.60</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Progression while on bevacizumab</P></TD> <TD align=3Dleft> <P class=3D"">18.53</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">13.14</P></TD> <TD align=3Dleft> <P class=3D"">18.02</P></TD> <TD align=3Dleft> <P class=3D"">0.36=9644.95</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Rebound</P></TD> <TD align=3Dleft> <P class=3D"">36.24</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">19.71</P></TD> <TD align=3Dleft> <P class=3D"">31.00</P></TD> <TD align=3Dleft> <P class=3D"">5.45=9674.88</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Change from start to after 1st cycle</P></TD> <TD align=3Dleft> <P class=3D"">−5.06</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4.57</P></TD> <TD align=3Dleft> <P class=3D"">−3.44</P></TD> <TD align=3Dleft> <P class=3D"">−14.84=960.55</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Change from 1st cycle to progression</P></TD> <TD align=3Dleft> <P class=3D"">9.56</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">13.97</P></TD> <TD align=3Dleft> <P class=3D"">6.84</P></TD> <TD align=3Dleft> <P class=3D"">−12.09=9639.62</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Change from progression to rebound</P></TD> <TD align=3Dleft> <P class=3D"">17.71</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">12.24</P></TD> <TD align=3Dleft> <P class=3D"">16.78</P></TD> <TD align=3Dleft> <P class=3D"">0.76=9649.68</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">FLAIR</P></TD> <TD align=3Dleft> </TD> <TD align=3Dchar char=3D"."> </TD> <TD align=3Dleft> </TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Start of bevacizumab</P></TD> <TD align=3Dleft> <P class=3D"">43.39</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">25.93</P></TD> <TD align=3Dleft> <P class=3D"">43.43</P></TD> <TD align=3Dleft> <P class=3D"">11.60=9684.70</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> After 1st cycle of bevacizumab</P></TD> <TD align=3Dleft> <P class=3D"">30.88</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">13.14</P></TD> <TD align=3Dleft> <P class=3D"">33.75</P></TD> <TD align=3Dleft> <P class=3D"">8.91=9648.72</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Progression while on bevacizumab</P></TD> <TD align=3Dleft> <P class=3D"">43.38</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">20.88</P></TD> <TD align=3Dleft> <P class=3D"">43.66</P></TD> <TD align=3Dleft> <P class=3D"">21.19=9690.12</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Rebound</P></TD> <TD align=3Dleft> <P class=3D"">64.39</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">24.61</P></TD> <TD align=3Dleft> <P class=3D"">55.30</P></TD> <TD align=3Dleft> <P class=3D"">29.45=96101.12</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Change from start to 1st cycle</P></TD> <TD align=3Dleft> <P class=3D"">−12.50</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">17.64</P></TD> <TD align=3Dleft> <P class=3D"">−7.23</P></TD> <TD align=3Dleft> <P class=3D"">−49.03=966.10</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Change from 1st cycle to progression</P></TD> <TD align=3Dleft> <P class=3D"">12.50</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">14.60</P></TD> <TD align=3Dleft> <P class=3D"">10.40</P></TD> <TD align=3Dleft> <P class=3D"">−2.46=96 44.06</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Change from progression to rebound</P></TD> <TD align=3Dleft> <P class=3D"">21.01</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">16.02</P></TD> <TD align=3Dleft> <P class=3D"">16.12</P></TD> <TD align=3Dleft> <P = class=3D"">2.09=9651.12</P></TD></TR></TBODY></TABLE></DIV></DIV> <P class=3D"">Clinical outcomes included a median time to progression = while on=20 bevacizumab of 198.5 days. The median OS of patients who presented = with=20 rebound recurrence was 47.5 days. The seven patients who were not=20 re-started on bevacizumab had an OS of 32 days, and those who were=20 re-started on this anti-angiogenic drug had an OS of 149 days=20 (Table <A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#Tab1">1</A>).=20 </P> <P class=3D"">Of the three patients who were re-started on bevacizumab = after the=20 rebound MRI, two demonstrated partial radiographic response and the = other=20 remained stable after one 8-week cycle. Only one out of the eight = patients who=20 were not re-started on bevacizumab had a stable first follow-up MRI. = This=20 patient received fractionated radiosurgery and one month of temozolomide = as=20 next-line therapy. </P></DIV></DIV> <DIV class=3D""><A name=3DSec10></A> <HR> <DIV class=3Dheading2>Conclusions</DIV> <P class=3D"">High-grade gliomas are very aggressive tumours with a poor = prognosis=20 even after treatment with standard post resection chemo-radiation = [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR1">1</A></CITE>].=20 Historically, data tells us that few respond to second-line therapy and=20 prognosis is grim. However, the introduction of the anti-VEGF humanized=20 recombinant monoclonal antibody, bevacizumab, has provided remarkable = response=20 rates never seen before with previous therapy regimens. As bevacizumab = use=20 increases, we gain insight into radiographic patterns of response and=20 progression as well as the changes observed after cessation of this=20 anti-angiogenic drug [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR18">18</A></CITE>].=20 </P> <P class=3D"">To our knowledge, this is the first report describing a = rebound=20 radiographic phenomenon after the abrupt discontinuation of bevacizumab = when=20 used as therapy for recurrent high-grade glioma. However, this = phenomenon has=20 been described in patients treated with bevacizumab for other medical=20 conditions. Matsumoto et al. reported rebound macular edema in = those with=20 retinal vein occlusion after bevacizumab cessation [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR19">19</A></CITE>].=20 Cacheux et al. reported a tumour growth doubling time after = bevacizumab=20 interruption of 2 to 5 weeks in a small cohort of patients with = metastatic=20 colorectal cancer treated with FOLFOX6 or FOLFIRI chemotherapy in = addition to=20 bevacizumab [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR18">18</A></CITE>].=20 Pre-clinical data reported by Mancuso et al., suggests that = residual=20 sleeves of basement membrane and pericytes after endothelial cell = degeneration=20 caused by bevacizumab treatment provide a =93scaffold=94 for rapid = tumour vascular=20 re-growth [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR16">16</A></CITE>].=20 Our data supports this effect as it shows a mean increase of 95.6% in = the=20 largest cross-sectional area of enhancement between the MRI at the time = of=20 bevacizumab failure and the rebound MRI. When compared to the original = tumour=20 size, the increase is 158%. The changes in increased FLAIR signal are = not quite=20 as dramatic. There is a mean increase of 48.4% between the abnormal = FLAIR signal=20 seen at the time of bevacizumab failure and the rebound MRI. These = changes were=20 observed at a median of 6 weeks after discontinuation of = bevacizumab=20 therapy. The major variations seen are primarily at a vascular level and = the=20 initial amount of improvement seen on contrast-enhanced sequences does = not=20 necessarily represent a proportional degree of tumour burden control. = </P> <P class=3D"">Clinically, our review showed that this rebound phenomenon = resulted=20 in severe clinical decline with a median OS of 47.5 days. Our = review also=20 suggests that those who are not re-started on bevacizumab after the = rebound MRI=20 do very poorly with a median survival of 32 days. The median OS of = those=20 re-started on bevacizumab was markedly better at 149 days. Six out = of the=20 11 total patients had a low functional status at the time of rebound = enhancement=20 seen on the MRI. Our review is limited by its retrospective nature along = with a=20 small number of selected patients. By using the MacDonald criteria our=20 measurements may underestimate the degree of change between MRIs, as = they only=20 compare images on the same 2-dimensional plane and do not take into = account the=20 depth of the tumour burden. More sophisticated imaging techniques = involving=20 volumetric analysis are being used to more accurately determine tumour = size=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR14">14</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR20">20</A></CITE>].=20 </P> <P class=3D"">The purpose of this review is to describe this phenomenon = and not to=20 determine the frequency or to closely examine which patients are = susceptible to=20 this rebound effect. However, we must note that 11 out of the 40 = patients=20 (27.5%) that failed bevacizumab therapy demonstrated rebound PD. Also, = 10 out of=20 those 11 (91%) initially showed PR while on bevacizumab, which is higher = than=20 the response rates previously reported. This may indicate that the = patients at a=20 higher risk are those who have the best initial response. Nonetheless, = our=20 review highlights the importance of finding ways to prevent this rapid=20 progression from occurring. One such manner may be to slowly taper the = dose or=20 increase the interval between treatment sessions with bevacizumab. </P> <P class=3D"">In conclusion, this analysis describes a rebound = phenomenon that=20 portends a dismal and rapid clinical decline. It also supports the = observed lack=20 of response to any subsequent therapies. However, all three of the = patients in=20 our study group who were re-started on bevacizumab therapy re-responded, = which=20 led to an improved OS. </P> <P class=3D"">A larger controlled study should be performed to follow up = on these=20 preliminary results and support or nullify this hypothesis.</P></DIV> <P></P> <HR> <H2><A name=3DBib1></A>References </H2> <TABLE> <TBODY class=3DCitation> <TR vAlign=3Dtop> <TD>1.</TD> <TD><A name=3DCR1></A>Stupp R, Mason WP, van den Brent MJ, Weller M, = Fischer=20 B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, = Curschmann J,=20 Janzer R, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross = JG,=20 Esenhauer E, Mirimanoff R (2005) Radiotherapy plus concomitant and = adjuvant temozolomide for glioblastoma. 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J Neurooncol 78:281=96283<BR><A=20 href=3D"http://dx.doi.org/10.1007/s11060-005-9097-6" = target=3D_blank><IMG=20 height=3D20 alt=3DSpringerLink=20 = src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/springer_link= .gif"=20 width=3D108 border=3D0></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD28Xpt1ylt7Y%253D&md5=3D6b56c74d2cc1005958a04b7538f679ef"=20 target=3D_blank><IMG height=3D20 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/chemport_link= .gif"=20 width=3D65 border=3D0></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D16554966"=20 target=3D_blank><IMG height=3D20 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/pubmed_link.g= if"=20 width=3D65 border=3D0></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>6.</TD> <TD><A name=3DCR6></A>Poon RT-P, Fan S-T, Wong J (2001) Clinical=20 implications of circulating angiogenic factors in cancer patients. = J Clin=20 Oncol 19:1207=961225<BR><A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD3MXhvFertrc%253D&md5=3D186e3dbe97f08bc3b9544ce245899b84"=20 target=3D_blank><IMG height=3D20 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/chemport_link= .gif"=20 width=3D65 border=3D0></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D11181687"=20 target=3D_blank><IMG height=3D20 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/pubmed_link.g= if"=20 width=3D65 border=3D0></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>7.</TD> <TD><A name=3DCR7></A>Yang JC, Haworth L, Sherry RM, Hwu P, = Schwartzentruber=20 DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA (2003) A = randomized=20 trial of bevacizumab, an anti-vascular endothelial growth factor = antibody,=20 for metastatic renal cancer. N Engl J Med 349:427=96434<BR><A=20 href=3D"http://dx.doi.org/10.1056/NEJMoa021491" = target=3D_blank><IMG height=3D20=20 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/crossref_link= .gif"=20 width=3D65 border=3D0></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD3sXms1Klu7w%253D&md5=3D4c7e8c2ec042ca07fcc27c106875d94b"=20 target=3D_blank><IMG height=3D20 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/chemport_link= .gif"=20 width=3D65 border=3D0></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D12890841"=20 target=3D_blank><IMG height=3D20 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/pubmed_link.g= if"=20 width=3D65 border=3D0></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>8.</TD> <TD><A name=3DCR8></A>Hurwitz H, Fehrenbacker L, Novotny W, = Cartwright T,=20 Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, = Ferrara=20 N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus=20 irinotecan, fluorouracil and leucovorin for metastatic colorectal = cancer.=20 N Engl J Med 350:2335=962342<BR><A=20 href=3D"http://dx.doi.org/10.1056/NEJMoa032691" = target=3D_blank><IMG height=3D20=20 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/crossref_link= .gif"=20 width=3D65 border=3D0></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD2cXks1Gjt74%253D&md5=3D1b6ed0a488376415c5146bf4e4d3fd76"=20 target=3D_blank><IMG height=3D20 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/chemport_link= .gif"=20 width=3D65 border=3D0></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D15175435"=20 target=3D_blank><IMG height=3D20 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/pubmed_link.g= if"=20 width=3D65 border=3D0></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>9.</TD> <TD><A name=3DCR9></A>Sandler A, Gray R, Perry MC, Brahmer J, = Schiller JH,=20 Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin = alone or=20 with bevacizumab for non-small cell lung cancer. 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Retina=20 27:426=96431<BR><A = href=3D"http://dx.doi.org/10.1097/IAE.0b013e31804a7af2"=20 target=3D_blank><IMG height=3D20 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/crossref_link= .gif"=20 width=3D65 border=3D0></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D17420693"=20 target=3D_blank><IMG height=3D20 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/pubmed_link.g= if"=20 width=3D65 border=3D0></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>20.</TD> <TD><A name=3DCR20></A>Ananthnarayan S, Bahng J, Roring J, Nghiemphu = P, Lai=20 A, Cloughesy T, Pope W (2008) Time course of imaging changes of = GBM during=20 extended bevacizumab treatment. 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From: Subject: 10.1007/s11060-010-0121-0 Date: Tue, 6 Apr 2010 21:32:04 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01CAD5D0.9A254C90" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01CAD5D0.9A254C90 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.html 10.1007/s11060-010-0121-0</TIT= LE> <META http-equiv=3DContent-Type content=3D"text/html; = charset=3DISO-8859-1"><LINK=20 href=3D"http://www.springerlink.com/config/css/A++_common.css" = type=3Dtext/css=20 rel=3DstyleSheet><LINK=20 href=3D"http://www.springerlink.com/config/css/content_A++_SpringerLink.c= ss"=20 type=3Dtext/css rel=3DstyleSheet> <META content=3D"MSHTML 6.00.6000.17023" name=3DGENERATOR></HEAD> <BODY class=3Dfor-print> <TABLE cellPadding=3D2 border=3D1> <TBODY> <TR class=3Dheader> <TD>Journal of Neuro-Oncology</TD></TR> <TR> <TD>=A9 Springer Science+Business Media, = LLC. 2010</TD></TR> <TR> <TD>10.1007/s11060-010-0121-0</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Clinical Study - Patient Study</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Rebound tumour progression = after the=20 cessation of bevacizumab therapy in patients with recurrent high-grade = glioma=20 </DIV> <P class=3DAuthorGroup>Richard M. Zuniga<SUP>1 <A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#ContactOfAuthor1"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/contact.gif" = border=3D0></A></SUP>, Roy Torcuator<SUP>1, 2</SUP>,=20 Rajan Jain<SUP>3</SUP>, John Anderson<SUP>4</SUP>,=20 Thomas Doyle<SUP>4</SUP>, Lonni Schultz<SUP>5</SUP> and=20 Tom Mikkelsen<SUP>1, 2</SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Henry Ford Health System, Hermelin = Brain Tumor=20 Center, 2799 W Grand Blvd, Detroit, MI 48202,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff2></A>(2) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, Henry Ford = Health=20 System, Detroit, MI, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff3></A>(3) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neuroradiology, Henry = Ford=20 Health System, Detroit, MI, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff4></A>(4) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Medical Oncology, Henry = Ford=20 Health System, Detroit, MI, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff5></A>(5) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Biostatistics and = Research=20 Epidemiology, Henry Ford Health System, Detroit, MI,=20 USA</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor1></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/contact.gif" = border=3D0></TD> = <TD><STRONG>Richard </STRONG><STRONG>M. </STRONG><STRONG>Zuniga= </STRONG><STRONG></STRONG><BR><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:rickzunigaperu@hotmail.com">rickzunigaperu@hotmail.com</A>= </TD></TR></TBODY></TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>2 July 2009 <STRONG>Accepted:=20 </STRONG>25 January 2010 <STRONG>Published online:=20 </STRONG>12 February 2010 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract </SPAN>After withdrawal of = bevacizumab=20 in patients with recurrent high-grade glioma, we have observed a rapid = tumour=20 re-growth or =93rebound=94 radiographic phenomenon with accelerated = clinical=20 decline. We retrospectively reviewed 11 patients treated at the Henry = Ford=20 Hermelin Brain Tumor Center with recurrent high-grade glioma who = demonstrated a=20 rebound progression pattern after the discontinuation of bevacizumab. = The=20 original tumour area-of-enhancement increased by a mean of 158%, when = compared=20 to the rebound magnetic resonance imaging. After rebound, no patients = (0/8)=20 showed a response to next-line treatments that did not include = bevacizumab. The=20 median survival of those re-treated with bevacizumab was 149 and = 32 days=20 for those who received other regimens. Abrupt discontinuation of = bevacizumab=20 after recurrence often leads to a dramatic rebound phenomenon and rapid = clinical=20 decline. Slow tapering of the bevacizumab dose after tumour progression = may=20 prevent this from occurring and improve responsiveness to next-line = therapies.=20 </DIV> <P class=3DKeyword><SPAN=20 class=3DKeywordHeading>Keywords </SPAN>Glioma - Beva= cizumab - Rebound - Recurrent=20 glioma - Glioblastoma </P> <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> <P class=3D"">High-grade gliomas are aggressive tumours with a poor = prognosis even=20 after treatment with standard post resection chemo-radiation. These = tumours=20 exhibit diffuse parenchymal infiltration and are highly angiogenic. The = landmark=20 clinical trial by Stupp et al., described a median survival of=20 14.6 months and a 2-year survival rate of 26% for those with = glioblastoma=20 multiforme (GBM) after undergoing surgical resection with subsequent = external=20 beam radiation therapy plus temozolomide as first line therapy [<CITE><A = href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR1">1</A></CITE>].=20 </P> <P class=3D"">Due to the highly infiltrative nature of these tumours, = recurrence=20 is essentially inevitable. After first-line treatment failure, = historical data=20 reports a dramatic decrease in overall survival (OS) to 25 weeks = for GBM=20 and 47 weeks for AA [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR2">2</A></CITE>].=20 However, agents that target multiple signaling pathways and critical = growth=20 factors essential for tumour angiogenesis have become a major focus of = interest=20 in experimental clinical studies. Vascular endothelial growth factor = (VEGF) is a=20 potent growth factor produced by tumour and stromal cells that = facilitates=20 migration, proliferation and survival of endothelial cells making it = essential=20 in tumour angiogenesis [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR3">3</A></CITE>].=20 VEGF is heavily overexpressed in high-grade gliomas and is directly = correlated=20 with tumour growth rate, metastatic potential and poor outcome [<CITE><A = href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR4">4</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR6">6</A></CITE>].=20 </P> <P class=3D"">Bevacizumab, an anti-VEGF recombinant humanized monoclonal = antibody,=20 has been found to be active in other solid tumours, such as breast, = non-small=20 cell lung and colorectal cancer, and renal cell cancer [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR7">7</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR10">10</A></CITE>].=20 Over the past several years bevacizumab has been studied in high-grade = gliomas=20 with encouraging results. A number of reports have described an = excellent=20 improvement in radiographic response and clinical outcome in patients = treated=20 with bevacizumab and the cytotoxic agent, irinotecan, for recurrent = high-grade=20 gliomas [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR11">11</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR14">14</A></CITE>].=20 Despite these encouraging results, the remarkable and rapid radiographic = response seen on MRI does not appear to lead to a proportional = improvement in=20 survival and very few show any response at all to next-line therapy = after=20 bevacizumab failure [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR15">15</A></CITE>].=20 </P> <P class=3D"">As we gain more experience using this agent in high-grade = gliomas,=20 we also learn more about what occurs after treatment failure. Mancuso=20 et al. conducted a laboratory research study with mice to address = the=20 reversibility of VEGF inhibition after cessation of anti-VEGF therapy. = It was=20 noted that even after a 50=9660% reduction of tumour vascularity, = =93empty sleeves=20 of basement membrane were left behind.=94 By day 7 after drug = withdrawal, tumours=20 were fully re-vascularized, suggesting that these remaining empty = sleeves of=20 basement membrane and pericytes are responsible for this tumour=20 revascularization. These basement membranes also serve as angiogenic = growth=20 factor storage sites and =93tracks=94 for tumour vascular regrowth = [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR16">16</A></CITE>].=20 </P> <P class=3D"">This rapid tumour re-growth has also been noted in some of = our=20 patients after treatment failure with bevacizumab. A dramatic = =93rebound=94=20 radiographic recurrence phenomenon has been observed that appears to = lead to a=20 rapid clinical decline. It has not been defined who is susceptible to = this=20 rebound effect and traditional radiographic criteria used to assess = response are=20 not good indicators of effective tumour control in patients treated with = VEGF=20 inhibitors [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR14">14</A></CITE>],=20 and cannot predict who may present with this aggressive form of = progression.=20 </P> <P class=3D"">These observations led us to conduct a retrospective = review of=20 selected patients with the objective of quantitatively describing this = rebound=20 phenomenon along with its clinical implications in terms of patient = outcome and=20 response to subsequent therapy regimens. </P></DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Methods</DIV> <DIV class=3D""><A name=3DSec3></A> <DIV class=3DHeading3>Patient selection</DIV> <P class=3D"">We performed a retrospective search of the Henry Ford = Hospital,=20 Hermelin Brain Tumor Center database for all patients with recurrent = high-grade=20 glioma treated with bevacizumab-based regimens from 11/15/2005 to = 12/31/2008 and=20 found 53 patients. At the time of analysis, 40 patients had progressed = while on=20 bevacizumab and required discontinuation of the drug. We identified 11 = patients=20 within this group who presented with a rebound progression of disease = (PD)=20 pattern after the discontinuation of bevacizumab. All of the patients = were=20 required to have a minimum KPS score of 60%, normal kidney and adequate = bone=20 marrow function to be eligible for initial treatment with bevacizumab.=20 </P></DIV> <DIV class=3D""><A name=3DSec4></A> <DIV class=3DHeading3>Treatment</DIV> <P class=3D"">Each patient was treated with bevacizumab plus irinotecan = IV=20 infusions given once every two weeks. The bevacizumab was administered = at a dose=20 of 10 mg/kg. The dosing for irinotecan was dependent on whether the = patients were receiving enzyme-inducing anti-epileptic drugs (EIAED). If = they=20 were taking an EIAED, they received 340 mg/m<SUP>2</SUP> of = irinotecan once=20 every two weeks. If they were not taking EIAEDs they received=20 125 mg/m<SUP>2</SUP> of irinotecan every two weeks. Three treatment = sessions constituted one-six-week cycle. After bevacizumab treatment = failure,=20 eight out of the 11 patients received next-line treatment regimens that = did not=20 include bevacizumab (erlotinib, imatinib, hydroxyurea, sirolimus, = fractionated=20 stereotactic radiotherapy and the clinical trial investigational drugs = MLN-518=20 [tyrosine kinase inhibitor] and EM-1421). After the demonstration of = rebound=20 recurrence on MRI, the three remaining patients were re-started on=20 bevacizumab-based regimens (i.e., one patient received irinotecan, one = received=20 carboplatin and one received alternate-dose temozolomide). </P></DIV> <DIV class=3D""><A name=3DSec5></A> <DIV class=3DHeading3>MRI assessment</DIV> <P class=3D"">The MRIs for all 11 patients were reviewed by the authors = and a=20 neuro-radiologist. All 11 patients had high quality and acceptable=20 post-gadolinium T1 weighted and FLAIR MRI sequences. We quantitatively = measured=20 and compared the largest cross-sectional area of enhancement and of = abnormal=20 FLAIR signal seen on MRI at four different time points: (1) Prior to the = initiation of bevacizumab; (2) after one cycle of bevacizumab; (3) at = the time=20 of bevacizumab failure, and (4) after discontinuation of the drug. </P> <P class=3D"">Treatment failure and response was defined using the = revised=20 MacDonald criteria [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR17">17</A></CITE>].=20 A new focus of enhancement outside of at least a 2-cm margin from the = index=20 lesion was defined as =93distant=94 PD. An increase of over 25% of the = largest=20 cross-sectional area of enhancement of the index lesion constituted a = local=20 pattern of PD. Rebound PD was defined as an increase of at least 50% in = the=20 largest cross-sectional area of enhancement on the rebound MRI compared = to the=20 one performed at the time of bevacizumab failure. The revised MacDonald = criteria=20 define complete response (CR) as complete resolution of all detectable = areas of=20 enhancement. Partial response (PR) is defined as at least a 50% decrease = in the=20 largest cross-sectional tumour area. All others were labeled stable = disease=20 (SD). </P></DIV> <DIV class=3D""><A name=3DSec6></A> <DIV class=3DHeading3>Measurements, endpoints, and statistical = analysis</DIV> <P class=3D"">All patients underwent serial interval MRIs with and = without=20 gadolinium contrast every 6=968 weeks after the discontinuation of=20 bevacizumab. Our end points include the median patient OS after the = rebound MRI=20 as well as the radiographic response rate when started on next-line = therapy.=20 </P> <DIV class=3DPara> <DIV class=3D"">Treating clinicians at our institution reported = end-point=20 outcomes. We determined the rate of response in patients who were = re-started on=20 bevacizumab, as well as those who were started on a different salvage = treatment=20 regimen. The Kaplan=96Meier method was used for end-point estimation = (Fig. <A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#Fig1">1</A>).=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2010_121_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/MediaObjects/= 11060_2010_121_Fig1_HTML.gif"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 1 </SPAN>Kaplan=96Meier showing=20 overall survival </DIV> <HR> </DIV></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec7></A> <HR> <DIV class=3Dheading2>Results</DIV> <DIV class=3D""><A name=3DSec8></A> <DIV class=3DHeading3>Patient population</DIV> <DIV class=3DPara> <DIV class=3D"">We reviewed 53 patients with recurrent high-grade glioma = treated=20 with bevacizumab-based regimens. At the time of analysis 11 (eight men = and three=20 women) out of the 40 patients who failed bevacizumab therapy because of = tumor=20 recurrence, demonstrated radiographic rebound PD after the = discontinuation of=20 bevacizumab. Of these 11 patients, eight had primary GBM, two had = secondary GBM,=20 and one had anaplastic oligodendroglioma. All had received at least one = prior=20 chemotherapy regimen before the administration of bevacizumab. The = median age of=20 our patient population was 56 years of age. The median baseline KPS = score=20 at the time of bevacizumab failure was 90%. The median KPS at the time = of=20 radiographic rebound was 60%. One of the patients rebounded on the first = MRI=20 after complete surgical resection of the area of enhancement seen at the = time of=20 bevacizumab failure. Patient characteristics are shown in Table <A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#Tab1">1</A>.<A=20 name=3DTab1></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 1 </SPAN>Demographic and=20 Medical History Information (<I>n</I> =3D 11) </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Variable</P></TH> <TH align=3Dleft> </TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Age</P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Mean (SD)</P></TD> <TD align=3Dleft> <P class=3D"">53.5 (11.3)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Median (Range)</P></TD> <TD align=3Dleft> <P class=3D"">56 (37 to 72)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Sex, N (%)</P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Male</P></TD> <TD align=3Dleft> <P class=3D"">8 (72.7%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Female</P></TD> <TD align=3Dleft> <P class=3D"">3 (27.3%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Pathology, N (%)</P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> GBM</P></TD> <TD align=3Dleft> <P class=3D"">8 (72.7%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Anaplastic oligodendroglioma</P></TD> <TD align=3Dleft> <P class=3D"">1 (9.1%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Mixed anaplastic oligoastrocytoma, = GBM</P></TD> <TD align=3Dleft> <P class=3D"">1 (9.1%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Oligodendroglioma, GBM</P></TD> <TD align=3Dleft> <P class=3D"">1 (9.1%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">KPS at start of Avastin</P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Median</P></TD> <TD align=3Dleft> <P class=3D"">90</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Range</P></TD> <TD align=3Dleft> <P class=3D"">60=96100</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">KPS at Rebound</P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Median</P></TD> <TD align=3Dleft> <P class=3D"">60</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Range</P></TD> <TD align=3Dleft> <P class=3D"">50=9690</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Survival after Rebound</P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Median</P></TD> <TD align=3Dleft> <P class=3D"">7 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> 95% confidence interval</P></TD> <TD align=3Dleft> <P class=3D"">4.3=9626.6 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Overall Survival (OS)</P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Median</P></TD> <TD align=3Dleft> <P class=3D"">10.8 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> 95% confidence interval</P></TD> <TD align=3Dleft> <P = class=3D"">7.7=9616.2 months</P></TD></TR></TBODY></TABLE></DIV></DI= V></DIV> <DIV class=3D""><A name=3DSec9></A> <DIV class=3DHeading3>Response analysis</DIV> <DIV class=3DPara> <DIV class=3D"">We assessed radiographic response to next-line treatment = after=20 bevacizumab failure. Prior to beginning therapy with bevacizumab, the = mean=20 cross-sectional area of contrast enhancement and of abnormal FLAIR = signal was=20 14.03 and 43.9 cm<SUP>2</SUP>, respectively. All but one of the 11 = patients=20 demonstrated at least partial radiographic response (PR) after one cycle = of=20 bevacizumab therapy. From the time of bevacizumab failure to the = subsequent=20 rebound MRI the mean largest cross-sectional area of enhancement and = increased=20 FLAIR signal went from 18.53 to 36.24 cm<SUP>2</SUP> and 43.38 to=20 64.39 cm<SUP>2</SUP>, respectively (Fig. <A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#Fig2">2</A>).=20 The mean interval between the MRI performed at the time of bevacizumab = failure=20 and the rebound MRI was 6.1 weeks (Table <A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#Tab2">2</A>).=20 <DIV class=3DFigure><A name=3DFig2></A><IMG=20 alt=3DMediaObjects/11060_2010_121_Fig2_HTML.jpg=20 src=3D"http://www.springerlink.com/content/4j4h71v1237202p0/MediaObjects/= 11060_2010_121_Fig2_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 2 </SPAN>Original = tumor area=20 seen on post-Gd T1 weighted (<B>a</B>) and FLAIR MRI (<B>e</B>) = sequences prior=20 to initiating therapy with bevacizumab in a patient with recurrent = high-grade=20 glioma. Post-Gd T1 weighted (<B>b</B>) and FLAIR MRI (<B>f</B>) = sequences that=20 demonstrate partial response after 1 six-week cycle of treatment with=20 bevacizumab. Post-Gd T1 weighted (<B>c</B>) and FLAIR MRI (<B>g</B>) = sequences=20 at the time of bevacizumab failure and subsequent cessation of = bevacizumab=20 therapy. Post-Gd T1 weighted (<B>d</B>) and FLAIR MRI (<B>h</B>) = sequences at=20 the time of =93rebound=94 progression demonstrating a dramatic increase = in area of=20 enhancement and abnormal FLAIR signal 6 weeks after cessation of = therapy=20 with bevacizumab </DIV> <HR> <A name=3DTab2></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 2 </SPAN>Descriptive=20 statistics for time between MRIs, contrast and FLAIR measurements at = each MRI=20 and change in contrast and FLAIR measurements between MRIs </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dchar char=3D"."> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Variable</P></TH> <TH align=3Dleft> <P class=3D"">Mean</P></TH> <TH align=3Dleft char=3D"."> <P class=3D"">S.D.</P></TH> <TH align=3Dleft> <P class=3D"">Median</P></TH> <TH align=3Dleft> <P class=3D"">Range</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Time</P></TD> <TD align=3Dleft> </TD> <TD align=3Dleft char=3D"."> </TD> <TD align=3Dleft> </TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Start of to after 1st cycle = bevacizumab</P></TD> <TD align=3Dleft> <P class=3D"">8.1 weeks</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">3.6</P></TD> <TD align=3Dleft> <P class=3D"">8 weeks</P></TD> <TD align=3Dleft> <P class=3D"">4=9617.9 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> After 1st cycle of bevacizumab to = progression</P></TD> <TD align=3Dleft> <P class=3D"">23.6 weeks</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">13.4</P></TD> <TD align=3Dleft> <P class=3D"">22.9 weeks</P></TD> <TD align=3Dleft> <P class=3D"">6=9649.9 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Progression to rebound</P></TD> <TD align=3Dleft> <P class=3D"">6.1 weeks</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">2.5</P></TD> <TD align=3Dleft> <P class=3D"">6 weeks</P></TD> <TD align=3Dleft> <P class=3D"">3=9610 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Contrast</P></TD> <TD align=3Dleft> </TD> <TD align=3Dchar char=3D"."> </TD> <TD align=3Dleft> </TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Start of bevacizumab</P></TD> <TD align=3Dleft> <P class=3D"">14.03</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">7.91</P></TD> <TD align=3Dleft> <P class=3D"">15.66</P></TD> <TD align=3Dleft> <P class=3D"">3.64=9628.6</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> After 1st cycle of bevacizumab</P></TD> <TD align=3Dleft> <P class=3D"">8.97</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">6.23</P></TD> <TD align=3Dleft> <P class=3D"">8.40</P></TD> <TD align=3Dleft> <P class=3D"">1.08=9617.60</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Progression while on bevacizumab</P></TD> <TD align=3Dleft> <P class=3D"">18.53</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">13.14</P></TD> <TD align=3Dleft> <P class=3D"">18.02</P></TD> <TD align=3Dleft> <P class=3D"">0.36=9644.95</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Rebound</P></TD> <TD align=3Dleft> <P class=3D"">36.24</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">19.71</P></TD> <TD align=3Dleft> <P class=3D"">31.00</P></TD> <TD align=3Dleft> <P class=3D"">5.45=9674.88</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Change from start to after 1st cycle</P></TD> <TD align=3Dleft> <P class=3D"">−5.06</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4.57</P></TD> <TD align=3Dleft> <P class=3D"">−3.44</P></TD> <TD align=3Dleft> <P class=3D"">−14.84=960.55</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Change from 1st cycle to progression</P></TD> <TD align=3Dleft> <P class=3D"">9.56</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">13.97</P></TD> <TD align=3Dleft> <P class=3D"">6.84</P></TD> <TD align=3Dleft> <P class=3D"">−12.09=9639.62</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Change from progression to rebound</P></TD> <TD align=3Dleft> <P class=3D"">17.71</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">12.24</P></TD> <TD align=3Dleft> <P class=3D"">16.78</P></TD> <TD align=3Dleft> <P class=3D"">0.76=9649.68</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">FLAIR</P></TD> <TD align=3Dleft> </TD> <TD align=3Dchar char=3D"."> </TD> <TD align=3Dleft> </TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Start of bevacizumab</P></TD> <TD align=3Dleft> <P class=3D"">43.39</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">25.93</P></TD> <TD align=3Dleft> <P class=3D"">43.43</P></TD> <TD align=3Dleft> <P class=3D"">11.60=9684.70</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> After 1st cycle of bevacizumab</P></TD> <TD align=3Dleft> <P class=3D"">30.88</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">13.14</P></TD> <TD align=3Dleft> <P class=3D"">33.75</P></TD> <TD align=3Dleft> <P class=3D"">8.91=9648.72</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Progression while on bevacizumab</P></TD> <TD align=3Dleft> <P class=3D"">43.38</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">20.88</P></TD> <TD align=3Dleft> <P class=3D"">43.66</P></TD> <TD align=3Dleft> <P class=3D"">21.19=9690.12</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Rebound</P></TD> <TD align=3Dleft> <P class=3D"">64.39</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">24.61</P></TD> <TD align=3Dleft> <P class=3D"">55.30</P></TD> <TD align=3Dleft> <P class=3D"">29.45=96101.12</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Change from start to 1st cycle</P></TD> <TD align=3Dleft> <P class=3D"">−12.50</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">17.64</P></TD> <TD align=3Dleft> <P class=3D"">−7.23</P></TD> <TD align=3Dleft> <P class=3D"">−49.03=966.10</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Change from 1st cycle to progression</P></TD> <TD align=3Dleft> <P class=3D"">12.50</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">14.60</P></TD> <TD align=3Dleft> <P class=3D"">10.40</P></TD> <TD align=3Dleft> <P class=3D"">−2.46=96 44.06</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Change from progression to rebound</P></TD> <TD align=3Dleft> <P class=3D"">21.01</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">16.02</P></TD> <TD align=3Dleft> <P class=3D"">16.12</P></TD> <TD align=3Dleft> <P = class=3D"">2.09=9651.12</P></TD></TR></TBODY></TABLE></DIV></DIV> <P class=3D"">Clinical outcomes included a median time to progression = while on=20 bevacizumab of 198.5 days. The median OS of patients who presented = with=20 rebound recurrence was 47.5 days. The seven patients who were not=20 re-started on bevacizumab had an OS of 32 days, and those who were=20 re-started on this anti-angiogenic drug had an OS of 149 days=20 (Table <A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#Tab1">1</A>).=20 </P> <P class=3D"">Of the three patients who were re-started on bevacizumab = after the=20 rebound MRI, two demonstrated partial radiographic response and the = other=20 remained stable after one 8-week cycle. Only one out of the eight = patients who=20 were not re-started on bevacizumab had a stable first follow-up MRI. = This=20 patient received fractionated radiosurgery and one month of temozolomide = as=20 next-line therapy. </P></DIV></DIV> <DIV class=3D""><A name=3DSec10></A> <HR> <DIV class=3Dheading2>Conclusions</DIV> <P class=3D"">High-grade gliomas are very aggressive tumours with a poor = prognosis=20 even after treatment with standard post resection chemo-radiation = [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR1">1</A></CITE>].=20 Historically, data tells us that few respond to second-line therapy and=20 prognosis is grim. However, the introduction of the anti-VEGF humanized=20 recombinant monoclonal antibody, bevacizumab, has provided remarkable = response=20 rates never seen before with previous therapy regimens. As bevacizumab = use=20 increases, we gain insight into radiographic patterns of response and=20 progression as well as the changes observed after cessation of this=20 anti-angiogenic drug [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR18">18</A></CITE>].=20 </P> <P class=3D"">To our knowledge, this is the first report describing a = rebound=20 radiographic phenomenon after the abrupt discontinuation of bevacizumab = when=20 used as therapy for recurrent high-grade glioma. However, this = phenomenon has=20 been described in patients treated with bevacizumab for other medical=20 conditions. Matsumoto et al. reported rebound macular edema in = those with=20 retinal vein occlusion after bevacizumab cessation [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR19">19</A></CITE>].=20 Cacheux et al. reported a tumour growth doubling time after = bevacizumab=20 interruption of 2 to 5 weeks in a small cohort of patients with = metastatic=20 colorectal cancer treated with FOLFOX6 or FOLFIRI chemotherapy in = addition to=20 bevacizumab [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR18">18</A></CITE>].=20 Pre-clinical data reported by Mancuso et al., suggests that = residual=20 sleeves of basement membrane and pericytes after endothelial cell = degeneration=20 caused by bevacizumab treatment provide a =93scaffold=94 for rapid = tumour vascular=20 re-growth [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR16">16</A></CITE>].=20 Our data supports this effect as it shows a mean increase of 95.6% in = the=20 largest cross-sectional area of enhancement between the MRI at the time = of=20 bevacizumab failure and the rebound MRI. When compared to the original = tumour=20 size, the increase is 158%. The changes in increased FLAIR signal are = not quite=20 as dramatic. There is a mean increase of 48.4% between the abnormal = FLAIR signal=20 seen at the time of bevacizumab failure and the rebound MRI. These = changes were=20 observed at a median of 6 weeks after discontinuation of = bevacizumab=20 therapy. The major variations seen are primarily at a vascular level and = the=20 initial amount of improvement seen on contrast-enhanced sequences does = not=20 necessarily represent a proportional degree of tumour burden control. = </P> <P class=3D"">Clinically, our review showed that this rebound phenomenon = resulted=20 in severe clinical decline with a median OS of 47.5 days. Our = review also=20 suggests that those who are not re-started on bevacizumab after the = rebound MRI=20 do very poorly with a median survival of 32 days. The median OS of = those=20 re-started on bevacizumab was markedly better at 149 days. Six out = of the=20 11 total patients had a low functional status at the time of rebound = enhancement=20 seen on the MRI. Our review is limited by its retrospective nature along = with a=20 small number of selected patients. By using the MacDonald criteria our=20 measurements may underestimate the degree of change between MRIs, as = they only=20 compare images on the same 2-dimensional plane and do not take into = account the=20 depth of the tumour burden. More sophisticated imaging techniques = involving=20 volumetric analysis are being used to more accurately determine tumour = size=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR14">14</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4j4h71v1237202p0/fulltext.htm= l#CR20">20</A></CITE>].=20 </P> <P class=3D"">The purpose of this review is to describe this phenomenon = and not to=20 determine the frequency or to closely examine which patients are = susceptible to=20 this rebound effect. However, we must note that 11 out of the 40 = patients=20 (27.5%) that failed bevacizumab therapy demonstrated rebound PD. Also, = 10 out of=20 those 11 (91%) initially showed PR while on bevacizumab, which is higher = than=20 the response rates previously reported. This may indicate that the = patients at a=20 higher risk are those who have the best initial response. Nonetheless, = our=20 review highlights the importance of finding ways to prevent this rapid=20 progression from occurring. One such manner may be to slowly taper the = dose or=20 increase the interval between treatment sessions with bevacizumab. </P> <P class=3D"">In conclusion, this analysis describes a rebound = phenomenon that=20 portends a dismal and rapid clinical decline. It also supports the = observed lack=20 of response to any subsequent therapies. However, all three of the = patients in=20 our study group who were re-started on bevacizumab therapy re-responded, = which=20 led to an improved OS. </P> <P class=3D"">A larger controlled study should be performed to follow up = on these=20 preliminary results and support or nullify this hypothesis.</P></DIV> <P></P> <HR> <H2><A name=3DBib1></A>References </H2> <TABLE> <TBODY class=3DCitation> <TR vAlign=3Dtop> <TD>1.</TD> <TD><A name=3DCR1></A>Stupp R, Mason WP, van den Brent MJ, Weller M, = Fischer=20 B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, = Curschmann J,=20 Janzer R, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross = JG,=20 Esenhauer E, Mirimanoff R (2005) Radiotherapy plus concomitant and = adjuvant temozolomide for glioblastoma. 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